Thymic involution and corticosterone level in Sandhoff disease model mice: new aspects the pathogenesis of GM2 gangliosidosis

Abstract

Sandhoff disease (SD) is a lysosomal disease caused by a mutation of the HEXB gene associated with excessive accumulation of GM2 ganglioside (GM2) in lysosomes and neurological manifestations. Production of autoantibodies against the accumulated gangliosides has been reported to be involved in the progressive pathogenesis of GM2 gangliosidosis, although the underlying mechanism has not been fully elucidated. The thymus is the key organ in the acquired immune system including the development of autoantibodies. We showed here that thymic involution and an increase in cell death in the organ occur in SD model mice at a late stage of the pathogenesis. Dramatic increases in the populations of Annexin-V(+) cells and terminal deoxynucletidyl transferase dUTP nick end labeling (TUNEL) (+) cells were observed throughout the thymuses of 15-week old SD mice. Enhanced caspase-3/7 activation, but not that of caspase-1/4, -6 ,-8, or -9, was also demonstrated. Furthermore, the serum level of corticosterone, a potent inducer of apoptosis of thymocytes, was elevated during the same period of apoptosis. Our studies suggested that an increase in endocrine corticosterone may be one of the causes that accelerate the apoptosis of thymocytes leading to thymic involution in GM2 gangliosidosis, and thus can be used as a disease marker for evaluation of the thymic condition and disease progression.

Supplementation of L-ascorbic acid and α-tocopherol alleviate arsenic induced immunotoxicities in thymus and spleen by dwindling oxidative stress induced inflammation

“…This elevated plasma corticosterone level led to reduction of absolute thymocyte and splenocyte counts in thymus and spleen respectively. It had been documented that elevated plasma corticosterone level led to thymic involution in SD mice [30] and splenic involution in Wistar-Kyoto rats [31]. These reports further attest our results shown in Fig.…”

“…In earlier studies it has been shown that arsenic caused to increase the secretion of ACTH and subsequently elevated the plasma corticosterone level [27][28]. It is well known that elevated plasma corticosterone level led to apoptosis of CD4 − /CD8 − T-cell, CD4 + /CD8 + T-cell, CD4 + and CD8 + T-cell and resulted in thymic involution [29] [30]. Elevated plasma corticosterone level also caused to involution of spleen [31].…”

Therapeutic Response in Feline Sandhoff Disease Despite Immunity to Intracranial Gene Therapy

“…cats treated with vectors expressing human Hex had marked cellular infiltrates apparent as vascular cuffs consisting primarily of B lymphocytes, whereas SD cats treated with the same vectors demonstrated little or no infiltrate. A differential immune response to the same AAV vectors may result from immune defects in affected animals, such as premature thymic involution caused in part by a ganglioside-mediated apoptotic cascade, as reported in cats with GM1 gangliosidosis [21][22][23] and in SD mice 24,25 and cats (data not shown). Though decreased thymus size is measurable only in late-stage disease, increased thymocyte apoptosis and other changes are present in early to middle disease stages, perhaps contributing to the diminished immune response of AAV-treated SD cats.…”